In rats chronically exposed to simulated altitude we have documented a hemoglobinemia which results from a splenic ineffective erythropoiesis. In the strain of Sprague Dawley rats studied (Hilltop), splenic erythropoiesis (SE) in intact but marrow erythropoiesis (ME) in splenectomized animals play the primary and comparable roles in the high altitude (HA) polycythemic response, ssggesting that activated SE may suppress ME. Erythropoietic responses to chronic exposure to mild HA are only moderate, but these reponses increase abruptly with severe altitude exposure. A correspondingly abrupt decrease in tissue PO2, however, is not evident. The polycythemic response to HA exposure was considerably more severe in Hilltop rats than in another group (Madison). The Hilltop animals, in which an inappropriate erythropoietic response was accompanied by a high mortality rate, may mimic chronic mountain sickness in humans. The objectives of this proposed study are (1) to test the hypothesis that hemolysis of "imperfect" erythrocytes is the mechanism for the hypoxia-induced ineffective erythropoiesis (HIIE) by determining the degradation in hypoxic recipients of 14C- and 59Fe-labeled erythrocytes prepared in hypoxic donors; (2) to evaluate the possibilities that HIIE results from extramedullary erythropoiesis by studying HIIE following chronic exposure to severe hypoxia in splenectomized rats; (3) to elucidate the nature of the suppressed ME by studying the effects of splenic extract from chronically hypoxic animals on the HA polycythemic response in splenectomized rats and by studying the tissue distribution of 125I-erythropoietin in chronically hypoxic rats; (4) to explore the mechanism determining the abrupt and inappropriate increase in the erythropoietic response to severe hypoxia by measuring ventilatory response, plasma erythropoietin, tissue erythrogenin and oxygenation, and (5) to explore the possibility that severe hypoxia may result in hemoglobinemia in man by analysis of plasma and urine of adult patients with severe hypoxic cardiopulmonary disorders and or neonates with the respiratory distress syndrome.